Dabigatran
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https://www.pradaxa.com/
Dabigatran
Indications and Usage Stroke and systemic embolism
Deep venous thrombosis
Pulmonary embolism
Primary prevention of venous thromboembolism
Dosage Forms and Strengths Capsules: 75 mg, 110 mg and 150 mg
Contraindications YES
Warnings and Precautions YES
Adverse Reactions YES
Drug Interactions YES
Use in Specific Populations NO
Recent Changes NO
Dabigatran developed by the pharmaceutical company Boehringer Ingelheim is an oral anticoagulant ("blood thinner") belonging to the class of direct thrombin inhibitors (DTIs). It is prescribed to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 6-10 days. It is also prescribed to reduce the risk of recurrence of DVT and PE in patients who have been previously treated, and for the prophylaxis of DVT and PE in patients who have undergone hip replacement surgery. Dabigatran is used as an alternative to oral anticoagulant warfarin and it is the first nonvitamin K antagonist test oralanticoagulant (NOAC) with a specific reversal agent Idarucizumab. [1][2][3]

FIELD INSIGHTS

  • Dr Tony Antoniou of St Michael's Hospital, Toronto, ON told heartwire from Medscape t that the absolute risk of drug interaction between Dabigatran and Statins is quite low, but the finding is still important because a lot of patients taking dabigatran are also on statins.
  • Dr Thomas Deering of Piedmont Heart Institute, Atlanta, GA said there are mechanistic reasons to think the drug interaction with statins might have validity, but "most important, we should not overreact and should figure out how to approach patients in a situation when we have one publication and not great, definitive data." and

RECENT TWEETS

DateAuthorComment
April 18, 2023RxDrugLabelsRx Package Insert: Dabigatran Etexilate, by Camber Pharmaceuticals, Inc. https://t.co/lDheeCbgce https://t.co/SO8ODVcAg2
April 18, 2023t4tobie@ObiakorNkem Hold me accountable,

The first time I heard of Dabigatran..

I said we don’t have until I saw the Pra… https://t.co/sepNcObJHa
April 18, 2023angryhacademic@HMellMac @Dimi62714097 No idea why, its what team clots used so thats what we used. I think dabigatran would be… https://t.co/Onx7G0lygz
April 18, 2023MedsLibDabigatran Etexilate (Camber Pharmaceuticals, Inc.): Dabigatran etexilate capsules are a direct thrombin inhibito… https://t.co/t5zIMINdWH
April 17, 2023PhunQuizGood morning. This is a #PhunQuiz Dose. Which is antineoplastic, specifically an alkylating agent?

A. Dabigatran

B… https://t.co/SeLl0HhE2L

RECENT NEWS ARTICLES

Date News Title Source
November 25, 2016 Dabigatran Bleed Risk With Lovastatin, Simvastatin in Study Raises Eyebrows Medscape
November 15, 2016 Dabigatran Reversal Agent’s Safety, Efficacy Affirmed With Updated Study Results TCTMD

INDICATIONS AND USAGE

Dabigatran is indicated for treatment and prevention in seven approved uses: [4][5]

Uses Indications
Stroke prevention in NVAF Dabigatran is indicated for the prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors, such as:
  • Prior stroke
  • Transient ischemic attack (TIA)
  • Age ≥75 years
  • Heart failure,
  • (NYHA Class ≥II),
  • Diabetes mellitus
  • Hypertension
Treatment of PE Dabigatran is indicated for the treatment of DVT and PE, and prevention of recurrent DVT and PE in adults
Treatment of DVT
Prevention of recurrent DVT
Prevention of recurrent PE
VTE prevention in total hip replacement elective surgery Dabigatran is indicated for primary prevention of venous thromboembolism (pVTEp) in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery
VTE prevention in total knee replacement elective surgery

HISTORY AND TIMELINE

  • March 26, 2002 - The Journal of Medicinal Chemistry published an article containing discovery highlights for the compound BIBR 1048 (dabigatran etexilate), orally absorbed double-prodrug which is serine protease thrombin active inhibitor obtained by converting compound BIRB 953 (dabigatran) with the addition of ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains. BIRB 953 was discovered from a panel of chemicals with the similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), known as a powerful inhibitor of various serine proteases, specifically thrombin, but also trypsin. [6]
  • March 18, 2008 - The European Medicines Agency (EMA) granted marketing authorisation for Dabigatran for the prevention of thromboembolic disease following hip or knee replacement surgery and NVAF. [7]
  • June 11, 2008 - Dabigatran received a Notice of Compliance (NOC) from Health Canada for the prevention of VTE in patients who have undergone elective total hip replacement or total knee replacement surgery. [8]
  • September 24, 2008 - The UK’s National Institute for Health and Clinical Excellence (NICE) has recommended Dabigatran within its marketing authorisation, as an option for the primary prevention of venous thromboembolism (VTE) in adults who have undergone elective total hip replacement surgery for elective total knee replacement surgery. [9]
  • October 6, 2010 - Dabigatran received an NOC from Health Canada for the prevention of stroke and systemic embolism in patients with AF, which makes Dabigatran the first new anticoagulant (anti-clotting drug) to be approved since warfarin was approved, which is more than 50 years. [10][11][12]
  • October 19, 2010 - The US Food and Drug Administration (FDA) approved Dabigatran for prevention of stroke in patients with NVAF. The FDA's Division of Cardiovascular and Renal Products recommended approval of Dabigatran 150 mg capsules for oral administration, but the 110 mg capsules did not receive marketing approval for reducing the risk of stroke and systemic embolism in patients with NVAF. Such decision was based on the review of the results from the RE-LY trial, after which the US FDA concluded there was no subgroup of patients for whom Dabigatran 110 mg was not inferior to dabigatran 150 mg. [13][14][15]
  • January 21, 2011 - The Ministry of Health, Labour and Welfare (MHLW) in Japan today approved Dabigatran for the prevention of ischemic stroke and systemic embolism in patients with NVAF. [16]
  • February 14, 2011 - The American College of Cardiology Foundation and American Heart Association added Dabigatran to their guidelines for management of NVAF with a class I recommendation. [17]
  • Aug 4, 2011 - The European Commission approved Dabigatran in the EU member states for the prevention of stroke and systemic embolism in adult patients with NVAF with one or more risk factors. The approval for the stroke prevention in AF patients is based on results from RE-LY®, one of the largest studies ever conducted in AF including over 18,000 patients. [18]
  • August 12, 2011 - The Japanese MHLW issued a press release requiring Boehringer-Ingelheim to add a boxed warning to their label regarding the risk of fatal hemorrhage based on several recently reported cases of death possibly associated with the Dabigatran. [19]
  • November 17, 2011 - The Boehringer Ingelheim released detailed data from the drug safety database concerning 260 cases of fatal bleeding linked to its drug Dabigatran. These events occurred between March 2008 and October 31, 2011. In response, the European Medicines Agency (EMA) has issued a statement saying that it believes the deaths need to be viewed in the context of Dabigatran's rapid uptake and increased awareness of possible side effects. [20] [21]
  • December 7, 2011 - The FDA initiated an investigation about serious bleeding events concerning Dabigitran stating that it continues to believe that Dabigitran provides an important health benefit when used as directed and recommends, that healthcare professionals who prescribe Dabigitran follow the recommendations in the approved drug label and that patients with AF should not stop taking Dabigatran without talking to their healthcare professional. [22]
  • March 15, 2012 - The UK’s NICE has recommended Dabigatran etexilate as a possible treatment to prevent stroke and systemic embolism in people with AF. [23]
  • June 06, 2012 - Boehringer Ingelheim updated the US prescribing information for dabigatran etexilate in line with the US FDA opinion that a 150mg dose of Dabigatran is superior to warfarin in reducing ischaemic and haemorrhagic strokes in patients with AF. This change is based on the results of the pivotal RE-LY® trial conducted on 18 000 patients with NVAF. [24][25]
  • Sep 07, 2012 - in Canada, the Boehringer Ingelheim changed the local trade name for Dabigitran (Pradax®) to Pradaxa® on request of the Canadian Health Authority. [26]
  • November 8, 2012 New data from the RELY-ABLE® study have provided additional support to the safety profile and efficacy of Dabigatran for stroke prevention in patients with AF over a period in excess of 2 years. [27]
  • December 19, 2012 - The U.S. Food and Drug Administration (FDA) informed health care professionals and the public that the blood thinner (anticoagulant) Dabigatran should not be used to prevent stroke or blood clots (major thromboembolic events) in patients with mechanical heart valves, also known as mechanical prosthetic heart valves. [28]
  • April 07, 2014 - The U.S. FDA has approved Dabigatran for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for five to 10 days, and reduction in the risk of recurrent DVT and PE in patients who have been previously treated. [29]
  • April 25, 2014 - The EMA has extended the indications for the Dabigatran to include treatment of DVT and PE, and prevention of recurrent DVT and PE in adults. [30]
  • May 13, 2014 - The FDA reported the results of a large study comparing Dabigatran to warfarin in 134,000 Medicare patients. The Agency concluded that Dabigatran is associated with a lower risk of overall mortality, ischemic stroke, and bleeding in the brain than warfarin. Gastrointestinal bleeding was more common in those treated with Dabigatran than in those treated with warfarin. The risk of heart attack was similar between the two drugs. The Agency reiterated its opinion that Dabigatran's overall risk/benefit ratio is favorable. [31]
  • July 26, 2014 - The British Medical Journal (BMJ) published a series of investigations that accused Boehringer of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. Review of internal communications between Boehringer researchers and employees, the FDA and the EMA revealed that Boehringer researchers found evidence that serum levels of Dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from health regulatory agencies because the data conflicted with their extensive marketing of Dabigatran as an anticoagulant that does not require monitoring. [32]
  • December 17, 2014 - The Boehringer Ingelheim announced that the NICE has approved Dabigatran for use by the NHS within its marketing authorisation for the treatment of DVT and PE and prevention of recurrent DVT and PE in adults. [33]
  • February 12, 2015 - The Health Canada published a Safety Review which evaluated the available information on the interaction between Dabigatran, an anti-blood clotting drug, and MULTAQ (dronedarone) or CORDARONE (amiodarone), both used to control abnormal heart rates. available evidence supported that bleeding-related side effects may be associated with the drug-drug interaction between Dabigatran and Dronedarone or Amiodarone. In order to address these safety concerns, Health Canada has reviewed the prescribing information for these drugs to include warnings regarding their possible interaction with Dabigatran. [34]
  • October 16, 2015 - The U.S. FDA granted accelerated approval to Praxbind (idarucizumab) for use in patients who are taking the anticoagulant Dabigatran during emergency situations when there is a need to reverse Dabigatran’s blood-thinning effects. [35]
  • December 04, 2015 - Researchers in New Zealand called electronic prompt to remind doctors to monitor renal function of elderly patients who are on Dabigatran for signs of bleeding. [36]
  • August 29, 2016 - Efficacy data from GLORIA™-AF Registry Program were presented at the European Society of Cardiology congress (ESC card-2016). First results from GLORIA™-AF Registry Program showed show that treatment with Dabigatran was associated with low incidences of stroke, major bleeding and life-threatening bleeding. These results are consistent with data seen in recently published studies assessing anticoagulant use in everyday clinical practice. GLORIA™-AF is one of the largest ongoing global registry programs examining the use of oral antithrombotics in real-world clinical practice. [37]

MECHANISMS OF ACTION

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

BOXED WARNINGS

The Dabigatran label carries a Boxed Warning to advise patients that: [38]

WARNING: (A) PREMATURE DISCONTINUATION OF DABIGATRAN INCREASES THE RISK OF THROMBOTIC EVENTS, and (B) SPINAL/EPIDURAL HEMATOMA


See full prescribing information for complete boxed warning


(A) PREMATURE DISCONTINUATION OF DABIGATRAN INCREASES THE RISK OF THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant, including Dabigatran, increases the risk ofthrom botic events. To reduce this risk, consider coverage with another anticoagulant if Dabigatran is discontinued for a reason other than pathological bleeding or completion of a course of therapy.


(B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may occur in patients treated with Dabigatran who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated.

Contraindications

Dabigatran is contraindicated in patients with:

  1. Hypersensitivity to the active substance or to any of these excipients:
Capsule fill
  • Tartaric acid
  • Acacia
  • Hypromellose
  • Dimeticone 350
  • Talc
  • Hydroxypropylcellulose
Capsule shell
  • Carrageenan
  • Potassium chloride
  • Titanium dioxide
  • Indigo carmine (E132)
  • Sunset yellow (E110)
  • Hypromellose
Black printing ink
  • Shellac
  • Iron oxide black (E172)
  1. Severe renal impairment (Creatine Clearance (CrCL) level < 30 mL/min), and therefore, before initiation of the treatment with Dabigatran renal function should be assessed by calculating the CrCL.
  2. Active clinically significant bleeding, because Dabigatran increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension) should be promptly evaluated and if there are any, use of Dabigatran should be discontinued.
  3. Lesion or condition with significant risk factor for major bleeding which may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
  4. Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances of switching anticoagulant therapy, or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
  5. Hepatic impairment or liver disease expected to have any impact on survival or with elevated liver enzymes ≥ 2 Upper Limit of Normal (ULN). No treatment experience is available for this subpopulation of patients, and therefore the use of Dabigatran is not recommended in this population.
  6. Concomitant treatment with systemic strong P-gp inhibitors like ketoconazole, cyclosporine, itraconazole and dronedarone that results in increasing Dabigatran plasma concentrations.
  7. Prosthetic heart valves requiring anticoagulant treatment, because of the risk of thromboembolic and bleeding events. [39][40][41][42]

ADVERSE REACTIONS

The most commonly reported side effect of dabigatran is GI upset. When compared to people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of GI bleeding was significantly higher. Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. The lower pH has previously been associated with dyspepsia; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding.[43]

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[44]

Reduced doses should be used in those with poor kidney function.[45]

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

COMPARISON CHART WITH OTHER DRUGS IN THE CLASS

In the class of new oral antiocoagulants (NOAcs), besides Dabigatran, in recent years, several drug have been introduced and approved, and more drugs are currently under development. These drugs have given patients and providers alternatives to heparin and warfarin, mainly for prophylaxis against stroke in patients with AF, prophylaxis/treatment of VTE and in treatment of acute coronary syndrome (ACS).

The NOACs fall into two broad categories: the oral direct factor Xa (FXa) inhibitors Rivaroxaban, Edoxaban and Apixaban, and the oral direct thrombin inhibitor Dabigatran. Other direct FXa inhibitor being investigated in clinical trial is Betrixaban which is pending for approval at the moment. [46] [47]
Characteristics [48] Dabigatran Warfarin Apixaban Rivaroxaban Betrixaban Edoxaban
Molecular weight

(Da)

628 308 460 436 452 548
Bioavailability (%) 6–7 98 66 63–79 40–80 50
tmax (h) 2–3 72–120 1–3 2–4 No records (NR) 1–3
t1/2 (h) 7–17 20–60 8–15 7–13 5 9–11
Protein binding (%) 35 99 87 95 NR 54
Food effect Delayed

absorption

Yes No Delayed absorption No No
Dosing regimen twice daily once daily twice daily once daily once daily once daily
Metabolism

/elimination

80% renal

20% liver

100% liver 25% renal

75% fecal

1/3 renal 2/3 liver 5% renal

95% liver

35% renal

65% liver

Substrate

CYP

No 2C9, 3A4 3A4 3A4, 2J2 No 3A4
Substrate

P-gp

Yes No Yes Yes No Yes
Food interaction No Yes (Vitamin K containing foods (such as salads and green vegetables) influence warfarin’s bloodth inning effect.

Patients on warfarin must carefully monitor what they eat to maintain a consistent vitamin K intake [49]

No No No NR
Monitoring

required

No INR No No No No
Target II II, VII, IX, X,

P-S, P-C

Xa Xa Xa Xa
Antidote Yes No No No No No
Typical effective dose 150 mg or 220 mg once daily (VTE prophylaxis)

75 mg or 150 mg twice daily (AF)

INR guided 2.5 bid (VTE prophylaxis) 10 mg once daily (VTE prophylaxis)

15 mg twice daily followed by 20 mg once daily (DVT treatment/prevention of recurrent VTE)

20 mg once daily (AF)

In

development

30 mg (VTE prophylaxis)
Drug interactions [50]
  • Anticoagulants
  • Platelet Inhibitors
  • Rifampin
  • Dronedarone/

Amiodarone

  • Diltiazem/Verapamil
  • Quinidine
  • Clarithromycin
  • Anticoagulants
  • Platelet Inhibitors
  • NSAIDs
  • SSRIs/SNRIs
  • Antifungals

(Ketoconazole, etc)/Antiretrovirals

  • Diltiazem/Verapamil
  • Amiodarone
  • Bactrim/Fluoroquinolones
  • Anticoagulants
  • Platelet Inhibitors
  • NSAIDs
  • Dipyridamole
  • Ritonavir
  • Antifungal Agents

(Ketoconazole, Posaconazole, etc)

  • Anticoagulants
  • Platelet Inhibitors
  • Macrolide Antibiotics
  • Prostacyclin Analogues
  • NSAIDs
  • Diltiazem/Verapamil
  • Rifampin/Phenytoin
  • Amiodarone/

Dronedarone

  • Ranolazine/Quinidine

P-gp inhibitors:

  • Ketoconazole
  • Amiodarone
  • Diltiazem [51]
  • Verapamil
  • Quinidine
  • Dronedarone
  • amiodarone
  • Digoxin or atorvastatin have relatively minor effects [52]
Approved indications Approved for VTE prevention after elective hip or knee replacement in adults and for prevention of stroke and systemic embolism in patients with NVAF. Approved for VTE prevention and treatment of the thromboembolic complications associated with AF and cardiac valve replacement,

and secondary prevention after myocardial infarction (MI).

Approved for VTE prevention after elective hip or knee replacement in adults.

Stroke prevention and SE in NVAF

Approved for VTE prevention after elective hip or knee replacement in adults, for prevention of stroke and systemic embolism in patients with NVAF, and for treatment of acute DVT and prevention of VTE recurrence. Has not been approved yet Approved for the treatment of DVT and PE following 5-10 days of initial therapy with a parenteral anticoagulant, to reduce the

risk of stroke and SE in patients with NVAF. [53]

Pharmacokinetics

BRAND NAMES BY COUNTRY

Dabigatran was first authorised in all member states of the European Economic Area (EEA) via centralised procedure. It is currently authorised and/or marketed in 96 countries under the trade names Pradaxa®, Pradaxar®, or Prazaxa®. [54]

Country Brand name

[55][56][57]

Australia; Canada; Switzerland; Chile; Egypt; Greece; Hong Kong; Hungary; Indonesia; India; Lebanon; Malaysia; New Zealand; Oman; Peru; Philippines; Portugal; Singapore; Slovenia; Thailand; United States; Vietnam; South Africa; Argentina; Belgium; Colombia; Costa Rica; Czech Republic; Germany; Denmark; Dominican Republic; Ecuador; Finland; France; United Kingdom; Georgia; Guatemala; Honduras; Croatia (Hrvatska); Ireland; Israel; Iceland; Italy; South Korea; Lithuania; Latvia; Nicaragua; Netherlands; Norway; Panama; Romania; Serbia; Russian Federation; Sweden; El Salvador; España, Spain; Austria; Bosnia & Herzegovina; Pradaxa®
Japan Prazaxa®
Mexico Pradaxar®

BOX IMAGES

Drug Market Box images
75 mg 100 mg 150 mg
Japan alt text alt text
EU and the rest of the world alt text alt text alt text
Mexico alt text alt text alt text
US alt text alt text
Drug images alt text alt text alt text
Doses (mg) 75 110 150
Drug Name Dabigatran 75 MG Dabigatran 110 MG Dabigatran 150 MG
Active ingredient(s) Dabigatran etexilate Dabigatran etexilate Dabigatran etexilate
Imprint R75 R110 R150
Color White Blue White and blue
Shape Capsule Capsule Capsule
Size 18 mm 18 mm 18 mm
Drug Label Author Boehringer Ingelheim

Pharmaceuticals Inc.

Boehringer Ingelheim

Pharmaceuticals Inc.

Boehringer Ingelheim

Pharmaceuticals Inc.

LAWSUITS

INSURANCE COVERAGE

PRICE

REFERENCES=

  1. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022512s027lbl.pdf
  2. ↑ http://www.medscape.com/viewarticle/807323
  3. ↑ http://products.boehringer-ingelheim.com/pradaxa/surgery-and-emergencies/praxbind
  4. ↑ http://products.boehringer-ingelheim.com/pradaxa/why-pradaxa/indications
  5. ↑ http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf
  6. ↑ http://pubs.acs.org/doi/abs/10.1021/jm0109513
  7. ↑ http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000829/human_med_000981.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125
  8. ↑ http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2008_pradax_114887-eng.php#toc2
  9. ↑ https://www.nice.org.uk/guidance/TA157/chapter/1-Guidance
  10. ↑ http://www.medicalnewstoday.com/releases/205933.php
  11. ↑ http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/regist/reg-innov-dr-eng.php
  12. ↑ http://www.montrealgazette.com/health/Approval+drug+heralds+momentous+advance+stroke+prevention/3739714/story.html
  13. ↑ http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2010/october_20_2010.html
  14. ↑ http://link.springer.com/article/10.1007%2Fs40256-015-0137-0
  15. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512orig1s000sumr.pdf
  16. ↑ http://www.pharmpro.com/news/2011/01/prazaxa%C2%AE-dabigatran-etexilate-approved-japan-stroke-prevention-atrial-fibrillation
  17. ↑ http://circ.ahajournals.org/content/123/10/1144.full
  18. ↑ http://www.fiercepharma.com/pharma/first-novel-blood-thinner-50-years-for-prevention-of-strokes-caused-by-common-heart-rhythm
  19. ↑ http://ss.pmda.go.jp/ja_all/muv_ajax.x?u=http%3A%2F%2Fwww.pmda.go.jp%2Ffiles%2F000155460.pdf%23page%3D18&p=18&t=&q=Prazaxa+2011+pmda+August+12%2C+2011&s=fUq9CeZy0C6AHILnUSW0FbI9jgmvzijs3NRnOl7tdNESUBPUMP1Od-2SPxc1wnSjSIZf5Fhtuhn1-t-2sTHePe7EB0KxSmNdEWM7FShicZxnWRzoIAdDgSq3dJP-lmUO4aXpMTG8gZ_MUBc8mS2qdy0HY5mYN2yRxI_L_cE5i3LwBv8PfsopBA..&lang=jp
  20. ↑ http://akampioneer.com/food-for-thought/food-for-thought-boehringer-ingelheim-puts-pradaxa-cards-on-the-table.html
  21. ↑ http://ss.pmda.go.jp/ja_all/muv_ajax.x?u=http%3A%2F%2Fwww.pmda.go.jp%2Ffiles%2F000155460.pdf%23page%3D18&p=18&t=&q=Prazaxa+2011+pmda+August+12%2C+2011&s=fUq9CeZy0C6AHILnUSW0FbI9jgmvzijs3NRnOl7tdNESUBPUMP1Od-2SPxc1wnSjSIZf5Fhtuhn1-t-2sTHePe7EB0KxSmNdEWM7FShicZxnWRzoIAdDgSq3dJP-lmUO4aXpMTG8gZ_MUBc8mS2qdy0HY5mYN2yRxI_L_cE5i3LwBv8PfsopBA..&lang=jp
  22. ↑ http://www.fda.gov/Drugs/DrugSafety/ucm282724.htm
  23. ↑ https://www.nice.org.uk/guidance/ta249
  24. ↑ http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2012/june_6_2012.html
  25. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022512s016lbl.pdf
  26. ↑ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000829/WC500148636.pdf
  27. ↑ http://www.boehringer-ingelheim.co.uk/news/medical_journalistpressreleases/rely-able_study_demonstratesbenefitsofpradaxadabigatranetexilate.html
  28. ↑ http://www.fda.gov/Drugs/DrugSafety/ucm332912.htm
  29. ↑ http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/04-07-14-fda-approves-pradaxa-dabigatran-etexilate-mesylate-treatment-reduction-risk-of-recurrence-deep-venous-thrombosis-pulmonary-embolism.html
  30. ↑ http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/000829/WC500165674.pdf
  31. ↑ http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm
  32. ↑ http://www.medscape.com/viewarticle/828750
  33. ↑ https://www.nice.org.uk/guidance/ta327
  34. ↑ http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/dabigatran_dronedarone_amiodarone-eng.php
  35. ↑ https://www.drugs.com/newdrugs/fda-approves-praxbind-idarucizumab-reversal-agent-anticoagulant-pradaxa-4278.html
  36. ↑ http://www.medsafe.govt.nz/profs/PUArticles/PDF/PrescriberUpdate_Dec2015.pdf
  37. ↑ http://www.xibucaijing.com/2016/0831/3391.html
  38. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022512s027lbl.pdf
  39. ↑ http://www.medsafe.govt.nz/profs/datasheet/p/Pradaxacap.pdf
  40. ↑ http://products.boehringer-ingelheim.com/pradaxa/using-pradaxa/contraindications
  41. ↑ http://www.medsafe.govt.nz/profs/datasheet/p/Pradaxacap.pdf
  42. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022512s027lbl.pdf
  43. ↑ Template:Cite journal
  44. ↑ Template:Cite journal
  45. ↑ 18/12/2014 Pradaxa -EMEA/H/C/000829 -II/0073
  46. ↑ http://www.just.edu.jo/DIC/Manuals/Comparison%20New%20Oral%20Anticoagulants%20%20With%20Warfarin.pdf
  47. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf
  48. ↑ http://www.just.edu.jo/DIC/Manuals/Comparison%20New%20Oral%20Anticoagulants%20%20With%20Warfarin.pdf
  49. ↑ http://files.www.clotconnect.org/Comparison_of_oral_anticoagulants_Final.pdf
  50. ↑ http://c.ymcdn.com/sites/www.leadingagemaryland.org/resource/resmgr/Docs/2015-04_MR_-_Anticoagulant_C.pdf
  51. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489817/
  52. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781304/
  53. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf
  54. ↑ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000829/WC500148636.pdf
  55. ↑ https://www.drugs.com/international/dabigatran.html
  56. ↑ http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000829/WC500148636.pdf
  57. ↑ http://www.boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/Pradaxa_name_Change_HCP_Letter.pdf

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